Late Breaking Abstract - Evaluation of the antifibrotic activity of bexotegrast, a dual αVβ6/αVβ1 integrin inhibitor, in precision-cut lung slices prepared from non-IPF interstitial lung disease explants

Bexotegrast is a dual inhibitor of TGF-β-activating integrins αVβ6 and αVβ1 currently in clinical development for the treatment of idiopathic pulmonary fibrosis (IPF). Preclinical evaluation of bexotegrast in precision-cut lung slices (PCLS) from IPF patient explants showed reduced fibrotic gene expression. In this study, we evaluated the antifibrotic activity of bexotegrast in PCLS generated from non-IPF interstitial lung disease (ILD) patients with progressive pulmonary fibrosis (PPF). Lung explants from patients with non-IPF ILD were obtained at the time of transplant and assessed histologically for levels of fibrosis (picrosirius red staining) and expression of αVβ6 (immunohistochemistry). PCLS were generated from fresh non-IPF ILD explants and treated with bexotegrast for 7 days. Gene expression changes were measured using the Nanostring platform. Non-IPF ILD explants from patients with rheumatoid arthritis-associated ILD, systemic sclerosis, hypersensitivity pneumonitis, and non-specific interstitial pneumonia had regions with high αVβ6-expressing cells overlapping with fibrosis. Treatment of fibrotic PCLS with bexotegrast significantly reduced collagen gene expression (COL1A1, -63%, p<0.0001; COL1A2, -50%, p<0.001), as well as markers of TGF-β-signaling (SERPINE1, -44%, p<0.001) and pathologic fibroblasts (CTHRC1, -48%, p<0.01). Inhibition of integrins αVβ6 and αVβ1 with bexotegrast reduced pro-fibrotic gene expression in human PCLS prepared from patients with non-IPF ILDs. These data support further investigation of the antifibrotic activity of bexotegrast in ILD associated PPF.